Process for the preparation of 4-[2-(dimethylamino)-ethoxy]2-methyl-5-(1-methylethyl)-phenol esters and their salts

(a) A solution of 1-chloro-2-dimethylaminoethane hydrochloride (540 g, 3.75 moles) is added slowly (2 h) and under vigorous stirring to a mixture of thymol (450 g, 3 moles) in toluene (4500 ml), 50% sodium hydroxide aqueous solution (2250 ml) and triethylbenzylamonium chloride (50 g), kept at 30° C.

After cooling, the inorganic layer is discharged whereas the organic layer is washed with water and dried over sodium sulphate.

The thus obtained solution contains 624.4 g (yield, 94.2%) of the product (II).

(b) Acetic anhydride (1300 ml) is added to 2430 ml of the solution obtained according to example 1a and containing 337 g (1.52 moles) of the product (II). To this solution is added 70% perchloric acid (340 ml) in about 30 minutes, mantaining the temperature below 45° C. The mixture is poured into water and made alkaline by addition of sodium hydroxide. The inorganic layer is discharged whereas the organic layer is washed with water and dried over sodium sulphate.

The organic solution contains 386.6 g (yield 97%) of the product (III) wherein R is CH 3 (IIIa).

(c) Trichloroacetic acid (480.7 g, 2.94 moles) and 80.4% meta-chloroperbenzoic acid (311.7 g, 1.47 moles) is added to a solution obtained according to example 1b.

The reaction mixture is mantained under stirring at 15° C. for 24 hours, then it is washed with diluted amonia, dried over sodium sulphate and the solvent is removed under reduced pressure.

The crude product is dissolved in anhydrous diethylether and the solution is saturated with hydrochloric acid gas. The solid product is collected by filtration, washed with diethylether and crystallized from isopropanol.

Yield, 287.5 g (0.91 moles; 62% of the theoretical amount) of Moxisylyte hydrochloride melting at 208°-210° C.

The overall yield as to thymol amounts to 56.6% of the theoretical amount.

In a 250 ml round-bottomed flask equipped with a refrigerant and a thermometer are introduced 20.8 g (0.08 moles) of IIIa, 140 ml of methylene chloride and 18.3 g (0.16 moles) of trifluoroacetic acid.

The solution is cooled at 15° C. under stirring and is added with 16.9 g (0.08 moles) of 82.3% m-chloroperbenzoic acid. The mixture is kept under stirring at 15° C. for 22 hours, then it is poured into water, made alkaline with sodium carbonate and extracted with diethylether.

The ethereal layer is dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The solid residue weights 16.6 g. The yield of the crude Moxisylyte (titre 89%) is 67% of the theoretical amount.

The product has been identified by TLC, GLC, IR and NMR tests in comparison with a pure sample.

The crude Moxisylyte is dissolved in anhydrous diethylether and the solution thus obtained is satured with hydrochloric acid gas.

The solid product is collected by filtration, washed with ethylether and crystallized from isopropanol.

It is thus obtained the hydrochloride of Moxisylyte melting at 208°-210° C.

The process of example 2 is carried out by reacting 5.2 g (0.02 moles) of IIIa in 30 ml of 1,2-dichloroethane with 5.7 g (0.04 moles) of BF 3 etherate and with 4.2 g (0.02 moles) of 82.3% m-chloro-perbenzoic acid for 22 hours at 15° C. Yield, 39% of the theoretical amount of Moxisylyte.

The process of example 2 is carried out by reacting 5.2 (0.02 moles) of IIIa in methylene chloride (30 ml) with 6.6 g (0.04 moles) of trichloroacetic acid and with 4.2 g (0.02 moles) of 82.3% m-chloro-perbenzoic acid for 7 hours at the boiling temperature (40° C.). Yield, 36% of the theoretical amount of Moxisylyte.

The process of example 2 is carried out by reacting 5.2 g (0.02 moles) of IIIa in 1,2-dichloroethane (30 ml) with 6.6 g (0.04 moles) of trichloroacetic acid and with 7.6 g (0.02 moles) of 20% peracetic acid for 22 hours at 15° C.

Yield, 39% of the theoretical amount of Moxisylyte.

The process of example 2 is carried out by reacting 5.2 g (0.02 moles) of IIIa in acetic acid (30 ml) with 6.6 g (0.04 moles) of trichloroacetic acid and with 7.6 g (0.02 moles) of 20% peracetic acid for 22 hours at 15° C. Yield, 30% of the theoretical amount of Moxisylyte.

The process of example 2 is carried out by reacting 5.2 g (0.02 moles) of IIIa in 30 ml of a mixture (1:2 v/v) of water and acetic acid, with 6.6 g (0.04 moles) of trichloroacetic acid and with 2.3 g (0.02 moles) of 30% hydrogen peroxide for 22 hours at 15° C. Yield, 45% of the theoretical amount of Moxisylyte.

The process of example 2 is carried out by reacting 5.8 g (0.02 moles) of 4-[2-(dimethylamino)-ethoxy]-2-methyl-5-(1-methylethyl)-1-butyroyl-1-benzene (IIIb), prepared in a manner similar to the one disclosed by example 1b, in 1,2-dichloroethane (30 ml) with 6.6 g (0.04 moles) of trichloroacetic acid with 4.2 g (0.02 moles) of 82.3% m-chloroperbenzoic acid for 22 hours at 15° C.

Yield, 53% of the theoretical amount of 4-[2-(dimethylamino)-ethoxy]-2-methyl-5-(1-methylethyl)-phenol, butyroxy ester. (Ib).

The crude product is dissolved in methanol (30 ml) and added with an 30% aqueous solution of sodium hydroxide (10 ml), the solution is warmed at 40°-45° C. for 30 minutes.

The reaction mixture is diluted with water and shaked with toluene, the toluene layer is separated and washed with 10% sodium hydroxide solution.

The aqueous phases are brought together and acidified with concentrated hydrochloric acid and then extracted with diethylether. The aqueous layer is then made alkaline with amonium hydroxide and extracted with diethylether.

The ethereal extracts are collected, dried over anhydrous sodium sulphate and the solvent is removed by evaporation under reduced pressure. The residue is dissolved in toluene, added with 5 ml of acetic anhydride and the thus obtained solution is refluxed for some hours.

After cooling, the solution is washed with water and with sodium bicarbonate, dried over anhydrous sodium sulphate and the solvent is removed by evaporation under reduced pressure.

It is so obtained the product Ia. (Moxisylyte)

Yield, 51.5% of the theoretical amount as to product IIIb.

To a solution of 4-[2-(dimethylamino)-ethoxy]-2-methyl-5-(1-methylethyl)-1-(p-nitrobenzoyl)-benzene (IIIc) prepared in a manner similar to the one disclosed by example 1b (1 g; 0.0027 moles) in glacial acetic acid (25 ml) 96% sulfuric acid (15 g; 0.147 moles) and 38% peracetic acid (4 g; 0.02 moles) are added. The reaction mixture is stirred at room temperature for 15 hours, then it is poured into water and extracted with diethylether.

The aqueous layer is separated, made alkaline with sodium bicarbonate and extracted with diethylether.

The ethereal extracts are collected and the solvent is removed by evaporation under reduced pressure.

It is so obtained the 4-[2-(dimethylamino)-ethoxy]-2-methyl-5-(1-methylethyl)-phenol p-nitrobenzoxy ester (Ic) (0.4 g). Yield 31% of the theoretical amount.